Cancer is the second leading cause of death in the United States, exceeded only by heart disease (Cancer Facts and Figures 2004, American Cancer Society, Inc.). Despite recent advances in cancer diagnosis and treatment, surgery and radiotherapy may be curative if a cancer is found early, but current drug therapies for metastatic disease are mostly palliative and seldom offer a long-term cure.
The AKT family regulates cellular survival and metabolism by binding and regulating many downstream effectors, e.g., Nuclear Factor-KB, Bcl-2 family proteins and murine double minute 2 (MDM2). Akt1 is known to play a role in the cell cycle. Moreover, activated Akt1 may enable proliferation and survival of cells that have sustained a potentially mutagenic impact and, therefore, may contribute to acquisition of mutations in other genes. Akt1 has also been implicated in angiogenesis and tumor development. Studies have shown that deficiency of Akt1 enhanced pathological angiogenesis and tumor growth associated with matrix abnormalities in skin and blood vessels. Since it can block apoptosis, and thereby promote cell survival, Akt1 is a major factor in many types of cancer.
Compound 3-(3-(4-(1-aminocyclobutyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (also known as compound 7) has been shown to modulate AKT genes and treat proliferation disorders, including cancer (US 2011/0172203 A1, herein after referred to as the '203 application). A small-scale synthesis of 3-(3-(4-(1-aminocyclobutyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (compound 7) has recently been published in the '203 application. The synthesis of the '203 application is impractical for producing large quantities of the compound and has several drawbacks.
Accordingly, there is a need for an improved synthetic route to 3-(3-(4-(1-aminocyclobutyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (compound 7) that is amenable to commercial production that is safe and simple.